PChronic Type 2 Diabetes Mellitus (T2DM) is often characterized by progressive ?-cell failure, leading to poor glycemic control, insulin dependence, and more severe diabetic complications. While hyperglycemia and inflammation are implicated in this ?-cell demise, the underlying mechanisms are unclear. One molecule strongly implicated in T2DM pathogenesis by genome-wide association studies is CD44, a cell-surface proteoglycan that mediates interactions between cells and the extracellular matrix. We have identified a novel role for CD44 and its primary ligand hyaluronan (HA) in the ?-cell failure associated with T2DM. We recently reported that both CD44 and HA are increased systemically in response to hyperglycemia and inflammatory cytokines in T2DM. Consistent with this, islet HA and CD44 levels are negligible in non-diabetic subjects but abundant in human cadaveric donors with T2DM. Similar findings are present in the db/db mouse model of the disease. Further, treatment of mice with the ?-cell toxin streptozotocin enhances ?-cell production of both HA and CD44. These data suggest that islet HA and CD44 are upregulated as an acute response to injury and that their prolonged expression in T2DM may be pathogenic. Our preliminary data strongly implicate HA and CD44 in the ?-cell failure that characterizes T2DM. Treatment of db/db mice with 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, clears islet HA deposits and promotes insulin production in these animals. Similarly, CD44-/-.db/db mice do not lose ?-cell mass or develop diabetes despite being morbidly obese. Moreover, both 4-MU treatment and deletion of CD44 are protective against low-dose streptozotocin. Together, these data point to decisive roles for HA and CD44 in ?-cell failure. Consistent with this, we have identified a role for HA and CD44 in responses to fibroblast growth factor 21 (FGF21), a key regulator of ?-cell function and homeostasis. ?-cells that express CD44 are less responsive to FGF21-mediated FGF receptor 1 (FGFR1) signaling, particularly in the presence of HA. However, the underlying mechanisms and their contribution to ?-cell failure in T2DM are unknown. In light of our exciting preliminary data, we hypothesize that CD44 drives ?-cell failure in T2DM via inhibition of FGF21 responses. Further, we propose that 4-MU, already an approved drug, could be repurposed to prevent ?-cell failure in T2DM. To test this hypothesis, in Aim 1 we will define the role of CD44 in ?-cell loss in T2DM. In Aim 2: we will then define the mechanisms involved in CD44-mediated effects on ?-cell FGF21 responses. Finally, in Aim 3 we will develop therapies that target HA/CD44 to preserve human ?-cell mass. Together, these Aims have the potential to reveal fundamental new pathways underlying the development of T2DM and to introduce novel treatments that will improve glycemic control in T2DM.